Unveiling the epigenomic mechanisms of acquired platinum-resistance in high-grade serous ovarian cancer
Menée à l'aide de lignées cellulaires ainsi que d'échantillons plasmatiques et d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer séreux ovarien de haut grade, cette étude identifie un mécanisme épigénomique impliqué dans la résistance des cellules cancéreuses aux sels de platine
Resistance to platinum-based chemotherapy is the major cause of death from high-grade serous ovarian cancer (HGSOC). We hypothesize that detection of specific DNA methylation changes may predict platinum resistance in HGSOC. Using a publicly available ?discovery? dataset we examined epigenomic and transcriptomic alterations between primary platinum-sensitive (n = 32) and recurrent acquired drug resistant HGSOC (n = 28) and identified several genes involved in immune and chemoresistance-related pathways. Validation via high-resolution melt analysis of these findings, in cell lines and HGSOC tumours, demonstrated the most consistent changes were observed in three of the genes: APOBEC3A, NKAPL and PDCD1. Plasma samples from an independent HGSOC cohort (n = 17) were analysed using droplet digital PCR. Hypermethylation of NKAPL was detected in 46% and hypomethylation of APOBEC3A in 69% of plasma samples taken from women with relapsed HGSOC (n = 13), with no alterations identified in disease-free patients (n = 4). Following these results, and using a CRISPR-Cas9 approach, we were also able to demonstrate that in vitro NKAPL promoter demethylation increased platinum sensitivity by 15%. Overall, this study demonstrates the importance of aberrant methylation, especially of the NKAPL gene, in acquired platinum resistance in HGSOC. This article is protected by copyright. All rights reserved.
International Journal of Cancer , article en libre accès, 2023